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BJA Advance Access originally published online on July 11, 2006
British Journal of Anaesthesia 2006 97(3):389-392; doi:10.1093/bja/ael176
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery{dagger}

R. S. Bondok1,* and A. M. Abd El-Hady2

1 Department of Anaesthesiology and Intensive Care, Ain-Shams University Hospitals Cairo, Egypt
2 Department of Orthopaedic Surgery, Ain-Shams University Hospitals Cairo, Egypt

*Corresponding author: Department of Anaesthesiology, Ain-Shams University Hospital, Ramses Street, Abbassia, Cairo, Egypt. E-mail: bondokrsa{at}hotmail.com

Accepted for publication May 31, 2006.


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background. Several medications are commonly injected intra-articularly for postoperative analgesia after arthroscopic knee surgery. Among the potentially efficient substances, magnesium could be of particular interest through its NMDA-receptor blocking properties.

Methods. A total of 60 patients undergoing arthroscopic knee surgery were randomly and double-blindly assigned to two groups to receive intra-articular injection of either 10 ml of magnesium sulphate (MgSO4) (50 mg ml–1) (Group M) or 10 ml of normal saline (Group C). Analgesic effect was evaluated by measuring pain intensity (visual analogue scale; VAS) 1, 2, 6, 8, 12, 18 and 24 h after operation and the time delay between MgSO4 or saline administration and the first requirement of supplementary analgesic medication by the patient (diclofenac).

Results. Intra-articular magnesium administration resulted in a significant reduction in pain scores in Group M compared with Group C 1, 2, 6 and 8 h after the end of surgery [1.7 (0.59), 2.2 (0.69), 2.8 (1.01) and 3.5 (1.10) in Group M; 8.0 (1.25), 5.9 (1.12), 4.4 (0.67) and 4.5 (1.13) in Group C, respectively]. A longer delay between intra-articular injection of the study medication and first administration of diclofenac was observed in Group M [667 (198) min] as compared with Group C [49 (13) min]. Total diclofenac consumption was significantly lower in Group M [37.5 (38.14) mg] than in Group C [117.5 (46.95) mg]. No early side-effects were noted.

Conclusion. Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery.

Keywords: analgesia, knee surgery; analgesia, postoperative; magnesium, intra-articular; receptor, NMDA; surgery, knee


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 REFERENCES
 
Various drugs are commonly administered intra-articularly to provide postoperative analgesia after arthroscopic knee surgery. Among them, bupivacaine,1 morphine2 and clonidine3 have been shown to reduce postoperative pain.

N-methyl-D-aspartate (NMDA) receptors play a major role in central nociceptive transmission, modulation and sensitization of acute pain states.4 In addition to their central location, recent studies identified NMDA receptors peripherally in the skin,5 muscles6 and knee joints,7 and found that they play a role in sensory transmission of noxious signals. In its inactive state, the NMDA receptor is blocked by the presence of a centrally positioned magnesium ion. Afferent activity in nociceptor fibres dislodges the central magnesium ion from the NMDA receptor, therefore allowing calcium influx into the cell.8 Magnesium can be considered as a physiological blocker of NMDA receptors.9 Magnesium therapy has been shown to be potentially beneficial in eclampsia,10 headache11 and acute migraine attacks.12 More recently, it has been demonstrated to reduce postoperative analgesic requirements.13 14

The aim of this study was to investigate the potential analgesic effect of magnesium when administered intra-articularly at the end of arthroscopic knee surgery.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 REFERENCES
 
The study was conducted in the Orthopaedic Department of Ain-Shams University Hospital. After approval from the local Ethics Committee and informed consent, 60 ASA I–II patients undergoing elective arthroscopic menisectomy were enrolled in the study. All surgical procedures were performed by the same surgeon (A.M. Abd El-Hady). After placement of routine monitors, induction of anaesthesia was achieved using i.v. thiopental (4 mg kg–1) and fentanyl (2 µg kg–1). No further opioid doses were administered during the surgical procedure. Anaesthesia was maintained with 60% nitrous oxide in oxygen and isoflurane (1.0–2.0% inspired concentration). Patients were randomly allocated to one of two groups using a computer-generated randomization list (n=30 for each group). Numbered, sealed and coded medical packs, each of which contained one syringe with active drug or placebo, were available. The anaesthetist, surgeon and observer were all unaware of the nature of the drug in each syringe, and the master codes were held by a personnel who did not participate in the observation. At the end of the surgery when skin was closed and before tourniquet release, the test solution was injected into the joint space. Group M patients received 10 ml of magnesium sulphate (MgSO4, 50 mg ml–1, that is 500 mg 5 ml–1 of a MgSO4 10% solution diluted to 10 ml using saline) intra-articularly; Group C patients received 10 ml of normal saline intra-articularly. All patients were blinded to the treatment. An observer blinded to the patient's study group assisted the patients in recording their pain scores. Pain intensity was assessed with a 10-point linear visual analogue scale (VAS). A score of 0 was described as no pain, and a score of 10 as the worse imaginable pain. Pain was scored 1, 2, 6, 8, 12, 18 and 24 h after operation.

Diclofenac sodium (75 mg) was administered i.v. as an analgesic supplement if the recorded VAS pain score was 5 or greater. Bearable pain period of time was considered as the time from intra-articular injection of the study drug to the first requirement of diclofenac. The total diclofenc consumption was also recorded. Side-effects such as flushing, sedation and reduction in heart rate and arterial pressure by more than 15% of baseline values were recorded at the same time points as those defined for VAS assessment.

Data were analysed using computer statistical software system SPSS® version 12.0 (SPSS Inc., Chicago, IL, USA). Numerical variables were examined for normality. Patient characteristics data, operative time and time delay between intra-articular injection and supplementary analgesic administration were analysed using two-tailed unpaired t-tests. Between group differences in pain scores and total diclofenac consumption were analysed using Mann–Whitney U-test. The number of patients requiring diclofenac was compared between groups using {chi}2-test with Yates correction. Descriptive data are expressed as mean (SD). Sample size was estimated using pain scores as the primary variable. Assuming a SD of 1 cm, we calculated a group size of 30 patients would be sufficient to detect a difference of 1 cm on the VAS at an alpha threshold of 0.007 with 90% power. A P-value lower than 0.05 was considered statistically significant and adjusted to a value of 0.007 when multiple comparisons were performed, according to Bonferroni.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 REFERENCES
 
All 60 patients in this study underwent an arthroscopic knee menisectomy. All participants were males. There was no statistical difference between the groups in terms of age [group M, 27 (4) yr; and group C, 25 (4) yr]. Mean operative duration was [32 (6) min] and [33 (4) min] in group M and C, respectively.

Pain scores were significantly lower in Group M than in Group C 1, 2, 6 and 8 h after the end of surgery [1.7 (0.59), 2.2 (0.69), 2.8 (1.01) and 3.5 (1.10) in Group M; 8.0 (1.25), 5.9 (1.12), 4.4 (0.67) and 4.5 (1.13) in Group C, respectively] (Fig. 1). The difference became less apparent thereafter.


Figure 1
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  		Fig 1 Bars represent the mean visual analogue pain scores 1, 2, 6, 8, 12, 18 and 24 h after surgery for each group. The extended bars represent SD. *Indicates a significant difference compared with control group.

 
A longer delay between intra-articular injection of magnesium or saline and first rescue diclofenac administration was observed in Group M [667 (198) min] as compared with Group C [49 (13) min] (P<0.0001) (Fig. 2). Total diclofenac consumption over the 24 h study period was significantly lower in Group M [37.5 (38.14) mg] than in Group C [117.5 (46.95) mg] (Table 1). No side-effects were reported during the first 24 h after surgery. Arterial pressure and heart rate did not change significantly. No patient complained of sedation.


Figure 2
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  		Fig 2 The analgesic duration in minutes in the two groups. The box represents the 25th–75th percentiles, and the mean is represented by the solid line. The extended bars represent the 10th–90th percentiles. Group M had a significantly longer time to first analgesic request than Group C (P<0.0001).

 

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  		Table 1 Total analgesic consumption mean (SD) and number of patients in each group requiring supplementary analgesia during the first 24 h after surgery. *Indicates a significant difference compared with control group

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
REFERENCES
 
In the present study, we have shown that intra-articular administration of MgSO4 (50 mg ml–1) at the end of arthroscopic knee surgery improves postoperative pain scores when compared with a situation in which no specific analgesic medication is administered to patients. It also increases the time to first rescue analgesic request and decreases the need for other analgesic medications.

In an attempt to improve fast rehabilitation after arthroscopic knee surgery, research has been directed toward new techniques for postoperative analgesia. Because systemic and intrathecal administration of magnesium enhances postoperative analgesia through its voltage-dependent block of NMDA receptors,13–15 we were interested in determining whether magnesium might provide analgesia when administered intra-articularly, especially with the evidence of NMDA receptor existence in the peripheral terminal of articular primary afferent fibres in the knee joint and on cellular elements in the joint, such as synoviocytes and immune cells; in which their activation were found to potentially play a role in nociception.7

A longer delay between intra-articular injection of magnesium and supplementary analgesic administration was observed in this study [667 (198) min]. When comparing our results with other commonly used intra-articular drugs, Reuben and Connelly found that the time for first analgesic request for intra-articular clonidine was 500 min, intra-articular bupivacaine 325 min and combined intra-articular clonidine and bupivacaine 700 min.3 In another study by Joshi and colleagues,16 the time for first analgesic request for intra-articular bupivacaine was 280 min, intra-articular clonidine and bupivacaine 600 min, intra-articular bupivacaine and morphine 720 min and combined intra-articular clonidine, bupivacaine and morphine was 950 min. In the study by Dal and colleagues,17 the time for first analgesic request for intra-articular ketamine was 109 min and for intra-articular neostigmine 113 min. It seems that intra-articular magnesium is much more efficient than any other sole intra-articular agent, and compares with combined agents such as intra-articular clonidine and bupivacaine, or intra-articular bupivacaine and morphine, in spite of different mechanisms of action.

Lower pain scores were observed after intra-articular administration of magnesium as compared with intra-articular saline during the first 8 h after the end of surgery, and both groups were comparable thereafter. This is probably because of the effect of random administration of diclofenac sodium on the time course of the VAS, combined with a physiological reduction in nociceptive input.

The mechanism of peripheral antinociceptive effect of NMDA antagonism has not been precisely defined. It has been hypothesized to occur through an analgesic and anti-inflammatory effect. NMDA antagonists reduce the excitability of nociceptive input terminals of C-fibres, which play a role in the central processing of pain.7 18 19 The anti-inflammatory action in the peripheral tissues occurs through antagonizing the release of inflammatory mediators such as histamine, cytokines and serotonin, which in turn excite nociceptors.7

The analgesic effect of intra-articular magnesium is evident. It seems likely that a local effect is at least partly responsible for this, as we did not observe the side-effects usually described after systemic administration of magnesium. Even though, it is still possible that magnesium analgesic effect occurs through systemic absorption. Further studies comparing groups receiving intra-articular magnesium and i.v. saline, intra-articular saline and i.v. magnesium and intra-articular saline with i.v. saline may help to resolve these questions.

Although these results are interesting and suggest a potential application for magnesium intra-articularly, there are concerns about exposing patients to the use of a drug in an area where there is little evidence to suggest its safety. MgSO4 has a product licence for i.v. administration. However, it may cause less pain on injection when administered intra-articularly than i.v. Furthermore, we have shown here that low concentrations of intra-articular magnesium are efficient for pain relief. Those concentrations may be safe for intra-articular tissues in the future.

In conclusion, attenuation of postoperative pain through intra-articular magnesium administration suggests a new alternative for pharmacological reduction of postoperative pain.


   Footnotes
 
{dagger}This article is accompanied by Editorial I. Back


   REFERENCES
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
1 Tuncer B, Babacan CA, Arslan M. The pre-emptive analgesic effect of intra-articular bupivacaine in arthroscopic knee surgery. Acta Anaesthesiol Scand 2005; 49:1373–7[CrossRef][ISI][Medline]

2 Rosseland LA, Stubhaug A, Skoglund A, Breivik H. Intra-articular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol Scand 1999; 43:252–6[CrossRef][ISI][Medline]

3 Reuben SS and Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intra-articular clonidine. Anesth Analg 1999; 88:729–33[Abstract/Free Full Text]

4 Woolf CJ. Somatic pain—pathogenesis and prevention. Br J Anaesth 1995; 75:169–76[Free Full Text]

5 Iwatsu O, Ushida T, Tani T, Lawand NB, Yamaoto H. Peripheral administration of magnesium sulfate and ketamine hydrochloride produces hypethesia to mechanical stimuli in humans. J Health Sci 2002; 48:69–72[CrossRef]

6 Cairns BE, Svensson P, Wang K, et al. Activation of peripheral NMDA receptors contributes to human pain and rat afferent discharges evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2003; 90:2098–105[Abstract/Free Full Text]

7 Lawand NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997; 324:169–77[CrossRef][ISI][Medline]

8 Dickenson AH. NMDA receptor antagonists as analgesics. In Fields HL and Liebeskind JC (Eds.). Progress in Pain Research and Management Volume I 1994.Seattle IASP Press pp. 173–87

9 Fawcet WJ, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br J Anaesth 1999; 83:302–20[Abstract/Free Full Text]

10 Eclampsia Trial Collaborative Group. Which anticonvulsant for women with preeclampsia? Evidence from the collaborative eclampsia trial. Lancet 1995; 345:1455–63[ISI][Medline]

11 Ginder S, Oatman B, Pollack M. A prospective study of i.v. magnesium and i.v. prochlorperazine in the treatment of headaches. J Emerg Med 2000; 18:311–15[CrossRef][ISI][Medline]

12 Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulphate in the treatment of acute migraine attacks. Headache 2001; 41:171–7[CrossRef][ISI][Medline]

13 Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. Effect of intraoperative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia 2003; 68:131–5[CrossRef]

14 Koinig H, Wallner T, Marhofer P, Andel H, Hoerauf K, Mayer N. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg 1998; 87:206–10[Abstract/Free Full Text]

15 Koo BN, Kil HK, Sin YS, Sung JW, Hong YW. The clinical effects of intrathecal MgSO4 on spinal anesthesia and postoperative epidural analgesia in total knee replacement. Reg Anesth Pain Med 2004; 29:11–13

16 Joshi W, Reuben SS, Kilaru PR, Sklar J, Maciolek H. Postoperative analgesia for outpatient arthroscopic knee surgery with intra articular clonidine and/or morphine. Anesth Analg 2000; 90:1102–6[Abstract/Free Full Text]

17 Dal D, Tetik O, Al tunkaya H, Tetik O, Doral MN. The efficacy of intra-articular ketamine for postoperative analgesia in outpatient arthroscopic surgery. Arthroscopy 2004; 20:300–5[ISI][Medline]

18 Jackson DL, Graff CB, Richardson JD, Hargreaves KM. Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol 1995; 284:321–5[CrossRef][ISI][Medline]

19 Liu H-T, Hollman MW, Liu W-H, Hoenemann CW, Durieux ME. Modulation of NMDA receptor function by ketamine and magnesium: Part I. Anesth Analg 2001; 92:1173–81[Abstract/Free Full Text]


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